Although tremendous progress has been made in the field of drug delivery, major challenges remain in controlled administration of insoluble and toxic hydrophobic drugs to target sites. A goal that continues to elude researchers is a functional system wherein a water-soluble container non-covalently binds hydrophobic guest molecules and releases them in a controlled manner in response to a specific trigger. Issues of encapsulation stability and versatility of the delivery vehicles continue to present major difficulties. When such a container is based on a nano-sized host, there is an even greater interest because of the potential in passive targeting of tumor tissue through the so-called enhanced permeability and retention (EPR) effect. (Peer, et al. 2007 Nat. Nanotechnol. 2, 751-760; Haag 2004 Angew. Chem. Int. Ed. 43, 278-282; Ganta, et al. 2008 J. Control. Release 126, 187-204; Allen, et al. 2004 Science 303, 1818-1822; Maeda, et al. 2000 J. Control. Release 65, 271-284.)
Water-soluble cross-linked polymer nanoparticles or nanogels that can sequester hydrophobic guest molecules within their interiors is of great interest in various applications ranging from delivery vehicles for therapeutics, to diagnostics to theranostics, among others. However, the classical preparative methods including microemulsion or inverse microemulsion ones do not conveniently allow the nanogels to be water-soluble and encapsulate hydrophobic guest molecules simultaneously. (Bachelder, et al. 2008 J. Am. Chem. Soc. 130, 10494; Oh, et al. 2007 J. Am. Chem. Soc. 129, 5939.)
Micellar assemblies are capable of non-covalently sequestering hydrophobic guest molecules in aqueous solution and solubilizing water-insoluble drug compounds within hydrophobic cores. These polymer micelles offer advantages in their nanoscopic sizes, which allow for passive targeting of certain disease sites through the enhanced permeability and retention effect. (Matsumura, et al. 1986 Cancer Res. 46, 6387-6392; Baban, et al. 1998 Adv. Drug Delivery Rev. 34, 109-119; Maeda, et al. 2000 J. Controlled Release, 65, 271-284; Duncan 2003 Nat. Rev. Drug Discovery, 2, 347-360.)
Micellar assemblies formed from small molecule surfactants, however, have inherent stability issues. Assemblies formed from amphiphilic polymers tend to exhibit enhanced stabilities, although they face significant complications because of a requisite concentration for assembly formation, which drastically limits the practicality of in vivo micelle utilization. Large dilution of injected micelles into the body can destabilize the self-assembling systems and cause uncontrolled and undesirable release of the encapsulated drug payload before arrival at the target site. Therefore, alternate strategies are desired to overcome such premature release. Moreover, the interaction between micelles and biological components, such as cellular membranes and blood components, can lead to premature release of the payload from the micelle core. (Bae, et al. 2008 J. Control. Release 131, 2-4; Chen, et al. 2008 Proc. Natl. Acad. Sci. U.S.A. 105, 6596-6601; Chen, et al. 2008 Langmuir 24, 5213-5217.)
Cross-linked polymer nanogels potentially provide both high encapsulation stability and potential for triggered release. Current synthetic methods for nanogel preparation are based on water-in-oil emulsion, in which inverse micelles, formed from surfactants in non-polar solvent, provide an aqueous interior as a reaction template for polymerization. These methods are complex and require multiple purification steps to remove unreacted monomers and surfactant materials that were used to stabilize the emulsion. (Bachelder, et al. 2008 J. Am. Chem. Soc. 130, 10494-10495; Sission, et al. 2009 Angew. Chem. Int. Ed. 48, 7540-7545; Kriwet, et al. 1998 J. Controlled Release 56, 149-158; Oh, et al. 2008 Prog. Polym. Sci. 33, 448-477.)
When a water-soluble polymer nanoparticle is targeted, inverse microemulsion-based synthesis is a preferred method. The continuous phase in the inverse microemulsion (water-in-oil emulsion) method is based on a hydrophobic solvent and, therefore, cannot be used to encapsulate hydrophobic guest molecules during nanoparticle formation.
A new emulsion-free method was recently developed for synthesis of cross-linked nanogels in aqueous media that allows facile hydrophobic guest encapsulation. This one pot synthesis is faster and easier than previous methods to achieve uniformly sized nanogels. (Ryu, et al. 2010 J. Am. Chem. Soc. 132, 8246-8247; Jiwpanich, et al. 2010 J. Am. Chem. Soc. 132, 10683-10685; Ryu, et al. 2010 J. Am. Chem. Soc. 132, 1722 7-17235.)
Improved polymer nano-assemblies and methods that allow systematic evaluation and fine-tuning of a broad range of properties and functionalities of nano-delivery vehicles are required to overcome the limitations and shortcomings of the existing technologies.